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Thymosin ß₁₀ Inhibits Angiogenesis and Tumor Growth by Interfering with Ras Function

¹ Molecular Therapy Research Center, Samsung Medical Center, School of Medicine, Sung Kyun Kwan University, Seoul, Korea and ² Department of Molecular Biology, Pusan National University, Busan, Korea

Requests for reprints: Je-Ho Lee or Seung-Hoon Lee, Molecular Therapy Research Center, Samsung Medical Center, Annex 8F, 50 Ilwondong, Kangnamgu, Seoul, Korea. Phone: 82-2-3410-6833; Fax: 82-2-3410-6829; E-mail: jeholee{at}samsung.co.kr; hoon61{at}smc.samsung.co.kr.

Thymosin ß₁₀ is a monomeric actin sequestering protein that regulates actin dynamics. Previously, we and others have shown that thymosin ß₁₀ acts as an actin-mediated tumor suppressor. In this study, we show that thymosin ß₁₀ is not only a cytoskeletal regulator, but that it also acts as a potent inhibitor of angiogenesis and tumor growth by its interaction with Ras. We found that overexpressed thymosin ß₁₀ significantly inhibited vascular endothelial growth factor–induced endothelial cell proliferation, migration, invasion, and tube formation in vitro. Vessel sprouting was also inhibited ex vivo. We further show that thymosin ß₁₀ directly interacted with Ras. This interaction resulted in inhibition of the Ras downstream mitogen-activated protein kinase/extracellular signal-regulated kinase kinase signaling pathway, leading to decreased vascular endothelial growth factor production. Thymosin ß₁₀ injected into a xenograft model of human ovarian cancer in nude mice markedly inhibited tumor growth and reduced tumor vascularity. In contrast, a related thymosin family member, thymosin ß₄, did not bind to Ras and showed positive effects on angiogenesis. These findings show that the inhibition of Ras signal transduction by thymosin ß₁₀ results in antiangiogenic and antitumor effects, suggesting that thymosin ß₁₀ may be valuable in anticancer therapy.

Key Words: thymosin ß₁₀ • angiogenesis • Ras • cancer therapy